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EP1044009B1 - Compositions contenant des produits fermentes a base de riz rouge et procedes associes - Google Patents

Compositions contenant des produits fermentes a base de riz rouge et procedes associes Download PDF

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Publication number
EP1044009B1
EP1044009B1 EP98954688A EP98954688A EP1044009B1 EP 1044009 B1 EP1044009 B1 EP 1044009B1 EP 98954688 A EP98954688 A EP 98954688A EP 98954688 A EP98954688 A EP 98954688A EP 1044009 B1 EP1044009 B1 EP 1044009B1
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Prior art keywords
red rice
rice
monascus
serum
fermentation
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English (en)
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EP1044009B8 (fr
EP1044009A2 (fr
EP1044009A4 (fr
Inventor
Mao Liang Room 619-623 ZHANG
Chi-Xiu Room 619-623 PENG
Yu-Fang Room 619-623 ZHOU
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Beijing Peking University WBL Biotech Co Ltd
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Peking University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/06—Fungi, e.g. yeasts
    • A61K36/062—Ascomycota
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/81—Solanaceae (Potato family), e.g. tobacco, nightshade, tomato, belladonna, capsicum or jimsonweed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/899—Poaceae or Gramineae (Grass family), e.g. bamboo, corn or sugar cane
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/14—Fungi; Culture media therefor
    • C12N1/145—Fungal isolates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/645—Fungi ; Processes using fungi
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/8215—Microorganisms
    • Y10S435/911—Microorganisms using fungi

Definitions

  • the invention relates to the fields of rice fermentation and treatment of hyperlipidemia. More particularly, the invention relates to red rice fermentation products and methods for producing improved red vice, and use of the products to treat high cholesterol levels and other disorders.
  • the invention relates to compositions comprising red rice fermentation products, that can be used as dietary supplements and/or therapeutic medicaments.
  • the compositions can be used to lower serum cholesterol and triglycerides in mammals.
  • the invention relates to methods of treating cardiovascular disorders and other diseases using the red rice fermentation products.
  • the invention relates to particular Monascus strains that yield fermentation products with the desired biological activities.
  • Red rice is known mostly for its use in food as a preservative and colorant, and its uses in the dye industry.
  • Red rice (known in Chinese as Hung-ch'u or Hongqu) has also been known and used for hundreds of years in China in rice wine making and as a food preservative.
  • red rice has been known as an ancient Chinese medicine or an ingredient in certain ancient Chinese prescriptions.
  • Red Rice was first used around the time of the Han Dynasty. Tao Gu, who lived in the age of Wudai after the Tang Dynasty, recorded "Red Yeast Rice Cooked with Meat,” in Qing Yi Lu. The method of making Red Rice was originally recorded in T'ien Kyng K'ai Wu and Pen Ts'ao Kang Mu, A detailed description of the medical applications of red rice was provided in the ancient Chinese pharmacopoeia, Pen Ts'ao Kang Mu, which was published during the Ming dynasty (1368-1644). In Pen Ts'ao Kang Mu, Red Rice is described as mild, nonpoisonous, and useful for treating indigestion and diarrhea.
  • Red Rice is also described as useful for improving blood circulation and promoting the health of the spleen and stomach. Furthermore, several "prescriptions" using red rice for treating aliments, such as indigestion, diarrhea, and heart and abdominal pains, are also provided in this ancient work.
  • Red Rice is specified to be used as a traditional Chinese medicine.
  • Red Rice is considered as additives for food and beverages, and has been widely used in the food processing industry for the production of such items as fermented bean curd, beer, and meat.
  • red rice is taught in another publication from the Ming dynasty, T'ien Kung K'ai Wu by Sung Ying-Hsing, which was published in 1637 A.D. (see pages 291-294 in English translation of this ancient writing, "Tien Kung K' ai Wu--Chinese technology in the seventeenth century," translated by E-tu Zen Sun and Shiou-Chuan Sun, The Pennsylvania State University Press 1966 ).
  • Red rice is described therein as useful for preserving the color and taste of fish or meat.
  • the manufacturing process used red wine mash and cooked nonglutinous rice as starting materials.
  • red rice the fermentation product of Monascus species
  • the red and yellow pigments of Monascus purpureus have been purified and extensively studied ( Fielding et al., 1961, J Chem Soc, 4579-4589 ).
  • the culture conditions and its effect on pigmentation of Monascus purpureus have also been studied ( Broder et al., 1980, J Food Sci, 45:567-469 ).
  • the Red Rice of the traditional methods has been shown to be of little value and thus has gradually fallen out of use in medical applications.
  • the traditional Red Rice has little effect of reducing blood lipids, and thus has never been used as a cholesterol lowering agent.
  • Lipids and lipoproteins play an essential role in transporting fat-derived metabolites between organs for absorption, metabolism, and distribution ( Felig et al., 1975, N Eng J Med, 293:1078-1084 ).
  • the susceptibility to dietary-induced elevations in blood lipids including cholesterol is extremely common.
  • the interaction of genetic predisposition and a high fat, high caloric diet coupled with underactivity can lead to heart disease, hypertension, hypertriglyceridemia, and diabetes in a significant proportion of the United States population.
  • High serum cholesterol is a major risk factor for coronary artery disease.
  • Cholesterol is a major component of atherosclerotic plaque.
  • Other associated lipid abnormalities including hypertriglyceridemia especially in the presence of lowered HDL cholesterol levels, have been recognized as contributing to the risk of cardiovascular disease.
  • the level of cholesterol in circulation results from the balance between production of apoB-100 particles and its removal from the circulation.
  • Cholesterol is synthesized from acetyl-CoA via a series of more than 20 enzymatic reactions. This biosynthetic pathway is mainly regulated by the activity ofHMG-CoA reductase (hydroxymethylglutaryl coenzyme A reductase), which catalyzes the reduction of HMG-CoA to mevalonate.
  • HMG-CoA reductase hydroxymethylglutaryl coenzyme A reductase
  • HMG-CoA reductase One class of compounds inhibits cholesterol biosynthesis by competing with a natural substrate (HMG-CoA) for the key enzyme in the cholesterol biosynthetic pathway, HMG-CoA reductase.
  • HMG-CoA a natural substrate
  • the first such hypocholesterolemic compound discovered was compactin, which was isolated from cultures of Penicillium citrinum by Akira Endo ( Endo et al., J Antibiotics (1975) 29:1346-1348 , see also US 3,983,140 , 4,049,495 , and 4,137,322 ).
  • the hypocholesterolemic activity of this compound was demonstrated in several animal species ( Tsujita et al., Atherosclerosis (1979) 32:307-313 ).
  • the active compound was also named mevinolin, lovastatin or Mevacor®; Tobert et al., J Clin Invest (1982) 69:913-919 ), and has been available in the United States since 1987 as a prescription drug. The efficacy and long term adverse effect of this active compound has been reviewed ( Tobert, Am J Cardiol, 62:28J-34J ). The isolated active compound, its derivatives and methods of production from Aspergillus have been reported; see U.S. patent nos. 4,231,938 , 4,342,767 , 4,294,926 , 4,319,039 , 4,294,926 , 4,294,846 , and 4,420,491 .
  • lipid regulating agents that have been used to treat hypertriglyceridemia, especially type IV and V hyperlipidemia, include nicotinic acid (e.g., niacin), and fibric acid derivatives (e.g., gemfibrozil and clofibrate).
  • nicotinic acid e.g., niacin
  • fibric acid derivatives e.g., gemfibrozil and clofibrate
  • the uses of such agents are restricted because of their side effects, for example, high doses of niacin may cause gastric irritability, hyperuricemia, hyperglycemia, pruritus, and gemfibrozil may lead to malignancy, gallbladder diseases, and abdominal pain.
  • the invention relates to a product of the fermentation of at least one Monascus strain that can be used as a dietary supplement or as a therapeutic medicament to lower both serum cholesterol and triglyceride levels in humans.
  • the invention is based, in part, on the surprising discovery that certain red rice products, i.e., the product of the fermentation of certain strains or mixtures of strains of Monascus, are effective at lowering not only the level of serum cholesterol but also the level of serum triglyceride in mammals, particularly humans. Since monacolin K and mevinolin are not known to be significantly effective in lowering serum triglyceride level, the beneficial effect of red rice products is likely to be related to other components in the fermentate.
  • red rice can be used as a natural dietary supplement or a medicament to treat or prevent a variety of diseases, including but not limited to cardiovascular diseases, diabetes, fatty liver conditions, stroke, cerebral thrombosis, hypotension, hypertension and obesity, and to modulate the circulating levels of lipids, such as cholesterol and triglyceride.
  • the present invention encompasses methods for treating or preventing these diseases in a human, which comprise administering to the human a therapeutically effective amount of a red rice fermentation product.
  • the present invention also encompasses methods for improving or maintaining cardiovascular health in a human comprising administering to an effective amount of red rice fermentation product.
  • the present invention further encompasses methods for reducing the serum cholesterol and serum triglyceride levels to normal levels in a human comprising administering to the human a therapeutically effective amount of a red rice fermentation product.
  • Red rice can also be used to treat or prevent a variety of ailments or symptoms as related to diseases of the cardiovascular system.
  • red rice can be manufactured in various dosage forms and formulations. Also disclosed are methods for manufacturing red rice which are based on the traditional fermentation procedures.
  • red rice fungi or “Monascus” as used herein refer to the prefermented organism, while the terms “red rice,” “red rice product”, “red rice extract” and the like refer to a product that results from the fermentation of at least one Monascus. Further, these latter terms include traditional and improved red rice products as described below. More specifically, “red rice product” as used herein refers to the product of fermentation, e.g., the fermentate of one or a mixture of Monascus fungus. A "lovastatin-producing Monascus strain is one which can be fermented to produce a product having a lovastatin content of at least 0.05%, preferably at least 2%.
  • the red rice product is the fermentation product of at least one of the following Monascus fungi set forth in the table below
  • Red rice is the fermentation product of one or a mixture of Monascus fungi, comprising Monascus ruber van Tieghem, Monascus Paxii Lingelsheim, Monascus Fuliginosus and Monascus albidus.
  • Red rice can also be the fermentation product of the following strains of Monascus fungi: Strains Accession No. Monascus albidus CGMCC No. 0317 Monascus ruber van Tieghem CGMCC No. 0315 CGMCC No. 0316 Monascus paxii Lingelsheim AS 3.4453 Monascus fuliginosus AS 3.569 AS 3.1098 AS 3.2091 AS 3.2093 AS 3.2134 IFFI 05035
  • traditional red rice refers to a red rice product which is the result of fermentation using a mixture of Monascus fungi that has been used traditionally to manufacture red rice.
  • "Traditional red rice” will generally contain less than about 0.005% lovastatin by weight.
  • an "improved red rice” is produced by fermentation using one or more natural or mutant strains of Monascus species, which yield a fermentate with improved biological or nutritional properties, e.g., higher hypocholesterolemic and hypotriglyceridemic activities than traditional red rice.
  • Improved red rice is sometimes referred to as Xuezhikang herein.
  • the red rice products of the present invention are red-purple powders that have a slightly bitter but mild and pleasant taste. Similarly, the red rice products have a pleasant odor.
  • the color and/or odor may vary with the fermentation process, the strains used and the processing steps.
  • the red rice products of the invention contain at least 0.05% lovastatin, more preferably at least about 2.0% lovastatin by weight.
  • the term "effective treatment” means the reduction of a particular symptom, or the significant change of a particular laboratory test toward the normal value.
  • symptoms are relieved by at least 30-70% and a laboratory test is moved at least 10% toward the normal value; more preferably symptoms are reduced by 70% and/or a laboratory test is moved at least 20% toward the normal value; most preferably, a treatment is effective if the symptoms are reduced by 90%, and/or laboratory parameters are returned to the normal value.
  • hypocholesterolemia means the presence of elevated levels of cholesterol in the blood.
  • terapéuticaally effective amount or “therapeutic dose” as used herein means the amount of a particular agent sufficient to provide a therapeutic benefit in the treatment or prevention of a disease, or in modulating the level of serum lipids and lipoproteins.
  • dietary supplement means an additional element that is added to the daily food intake of a mammal, usually a human.
  • the invention relates to compositions comprising the product of the fermentation of at least one Monascus species. These compositions are useful for reducing the levels of both serum cholesterol and serum triglycerides in mammals, and in particular humans. In addition, the compositions are useful for modulating the levels of both serum cholesterol and triglycerides to maintain healthy levels despite intrinsic (e.g. aging) or extrinsic (e.g. stress) factors that affect serum cholesterol and triglyceride levels.
  • the compositions and methods of the present invention are based, in part, on the discovery that the fermentate of Monascus species display hypocholesterolemic properties and also, unexpectedly, the ability to lower serum triglyceride levels.
  • red rice products Since monacolin K is known not to be significantly effective in lowering serum triglyceride level, the beneficial effect of red rice products must be related to other components of the fermentate. The ability of red rice products to lower serum triglyceride level provides the an with a unique, natural alternative to the use of prescription hypocholesterolemic compounds.
  • red rice can be prepared by traditional fermentation procedures or by modification of the traditional procedures.
  • red rice can be prepared by the fermentation of washed and cooked nonglutinous rice using red wine mash, natural juice of Polygonum grass, and alum water.
  • the rice is fermented in open air for 7 days on bamboo trays under very clean conditions.
  • the rice changes its color from white to black, black to brown, brown to red and then red to yellow, which is then harvested as red rice.
  • nonglutinous rice can be fermented in a hole in the ground lined by bamboo mats, which is securely covered. Fermentation is allowed to take place underground for one year or more, up to four years.
  • the traditional method has been improved by use of modem fermentation techniques and equipment to more precisely control temperature, pH, pressure and other fermentation parameters, which, inter alia , reduces the time of fermentation.
  • the key feature of the improved red rice preparation is that it contains active ingredients that can prevent or treat hyperlipidemia and related cardiovascular diseases.
  • the preparations can be made as follows:
  • the carbon source can be rice (polished long-grain nonglutinous rice, polished round-grain nonglutinous rice, polished glutinous rice, red rice, and black rice), millet, barley, wheat, or corn. Additionally sugar and substances containing sugar can be used. Organic compounds such as glycerine and glyceride can also be used in the media preparations. For each 100 g of polished round-grained nonglutinous rice, 30-80 ml of culture medium are added.
  • the culture media's key feature is that the carbon source is selected from the group consisting of cereals, sugar, and organic compounds, the source of nitrogen is selected form the group consisting of beans (e.g.
  • media preparations of the invention are listed below:
  • the pH is adjusted to 3.0-5.0. and the mixture is steam sterilized (121 °C).
  • the mixture is cooled to 40 °C, and the rice is inoculated with the a Monascus strain of the invention.
  • the Monascus purpureus Went strain CGMCC No. 0272 is added and cultured at 15-35°C for 9 days.
  • Fermentation of the rice mixture is preferably carried out at a temperature of 15-35°C, most preferably 20-28°C, for over 4 days, most preferably 9 days or more, until the formation of Red Rice is noted. Any one of a number of methods of fermentation, well known to one of skill in the art, can be used.
  • an Erlenmeyer flask, tray, or ventilated fermentation bed can be used as fermentation facilities.
  • the fermentation broth is drained and discarded, while the solid residue is sterilized by heat (for example, by high pressure steam).
  • the fermentation product is sterilized at a temperature of 69-121°C, and dried.
  • This dried product can be ground.
  • Standard mesh sizes for the production of capsules, tablets, powders and suspensions are well known in the art.
  • the improved red rice of the invention can be ground to 80 mesh under vacuum at a temperature of approximately 60-80°C, and the powdered product recovered.
  • This product can be used directly in the various compositions and formulations provided by the present invention. For example, it can be filled into capsules.
  • the 80 mesh ground product can further be ground to 200 mesh.
  • the 200 mesh powder can then formulated into tablets using standard methodologies.
  • liquid or syrup formulations of red rice can be made using conventional procedures.
  • the dried crushed red rice powder can be further processed, e.g., extracted with organic solvents, such as but not limited to, alcohols (e.g. 75-90% ethanol) to remove starch and/or agar.
  • organic solvents such as but not limited to, alcohols (e.g. 75-90% ethanol) to remove starch and/or agar.
  • the extract can be used in the various compositions and formulations as provided by the present invention.
  • the extracted product can further be concentrated under a vacuum and evaporated (60-80°C, 0.06-0-08 MPa) until dry. This provides an exceptionally useful supplement at very low cost.
  • an "improved red rice” is produced by fermentation using one or more natural or mutant strains of Monascus species, which yield a fermentate with improved biological or nutritional properties, e.g., higher hypocholesterolemic and hypotriglyceridemic activities than traditional red rice.
  • the improved red rice of the invention comprises Monascus albidus CGMCC NO 0317; Monascus ruber van Tieghem CGMCC No 0315, CGMCC No 0316, Monascus paxii Lingelsheim AS 3.4453, Monascus fuliginosus AS 3.569, AS 3.1098, AS 3.2091, AS 3.2093, AS 3.2134 and IFFI 05035. (Chinese Microorganism Strain Index, 1992, China Microorganism Collection Committee).
  • Lovastatin in red rice may be extracted using 10 ml of 75% EtOH at ambient temperature.
  • the extract (2 ml) is treated with 1 ml 0.06 M NaOH in 75% EtOH for 30 min, then with 1 ml 0.06 N H 3 PO 4 (in 75% EtOH), and the mixture applied to a C 18 HPLC column (150 x 4.60 mm), and developed with 0.02 N H 3 PO 4 , (in 70% MeOH) to quantify the amount of lovastatin present.
  • Red rice can be used as a natural dietary supplement or a pharmaceutical medicament to prevent illness (maintain health) or to treat or a variety of diseases, including but not limited to cardiovascular diseases, diabetes, stroke, hypertension and obesity, and to modulate the circulating levels of lipids and lipoproteins, such as cholesterol and triglycerides. Red rice can also be used to treat or prevent a variety of symptoms related to these above-mentioned diseases and associated with poor cardiovascular health due to aging and other intrinsic and extrinsic factors.
  • cardiovascular diseases may include but are not limited to myocardial infarction, coronary heart disease, atherosclerosis, arteriosclerosis.
  • the present invention includes the treatment or prevention of cerebrovascular disease such as stroke, memory loss due to stroke, and cerebral thrombosis.
  • the present invention also encompasses a composition comprising a therapeutically effective amount of a red rice product, for example 2-4 grams per day, useful in humans for the treatment or prevention of hyperlipidemic disease, cardiovascular disease, cerebrovascular disease, hypertension, hypotension, diabetes, fatty liver conditions, or obesity, or a combination thereof.
  • the present invention further encompasses a composition comprising a therapeutically effective amount of a red rice product, useful for the modulation of serum lipid and lipoprotein levels in a human in need of therapy to maintain the lipid and lipoprotein levels within a healthy normal range.
  • the composition is adapted for use in the treatment or prevention of hypertriglyceridemia.
  • such a composition is used for reducing serum cholesterol and serum triglyceride levels in humans.
  • the present invention further encompasses a composition comprising a therapeutically effective amount of improved red rice product, useful for the treatment of any one of the following symptoms: shortness of breath; asthenic breathing; lethargy; dizziness; chronic headache; chest pain and tightness; heartache; loss of appetite; limb swelling; tightness and distention.
  • the improved red rice of the invention and preparations of the improved red rice contain statinoid compounds, i.e. hydroxy-acid Lovastatin and lactone Lovastatin.
  • the above-mentioned Monascus strains when cultured under the appropriate fermentation conditions, have an increased content of the statinoid compounds.
  • the increase in the statinoid compounds reduces serum cholesterol and serum triglycerides, while, increasing high-density lipoprotein cholesterol simultaneously.
  • the red rice of the invention can be employed to treat hyperlipidemia and other related cardio-cerebrovascular diseases, such as atherosclerosis, coronary heart disease, myocardial infarction, diabetes, hypertension, and cerebral embolism, among others.
  • hyperlipidemia and other related cardio-cerebrovascular diseases, such as atherosclerosis, coronary heart disease, myocardial infarction, diabetes, hypertension, and cerebral embolism, among others.
  • the present invention provides a method for producing improved red rice, said method comprises: providing a lovastatin-producing Monascus strain selected from the group consisting of Monascus albidus CGMCC No. 0317; Monascus ruber van Tieghem CGMCC No. 0315, CGMCC No. 0316; Monascus paxii Lingelsheim AS 3.4453, Monascus fuliginosus AS 3.569, AS 3.1098, AS 3.2091, AS 3.2093, AS 3.2134 and IFFI 05035. Culturing said Monascus strain in a culture medium comprising rice at a temperature of 15 °C to 35 °C for a period of 2 to 20 days to provide crude red yeast rice; and drying said crude red rice to provide improved red rice.
  • a lovastatin-producing Monascus strain selected from the group consisting of Monascus albidus CGMCC No. 0317; Monascus ruber van Ti
  • compositions for treating a human afflicted by a variety of diseases, disorders and symptoms In addition to treatment of a human disease, the compositions of the invention can also be used for preventive treatment in a person susceptible to such diseases, disorders or symptoms.
  • the invention encompasses compositions for treatment of hyperlipidemic disease, cardiovascular disease, cerebrovascular disease, hypertension (hereditary and non-hereditary), hypotension, angina, stroke, diabetes, fatty liver conditions, or obesity, or a combination thereof in a human.
  • the invention also encompasses compositions for preventing hyperlipidemic disease, cardiovascular disease, cerebrovascular disease, hypertension, hypotension. angina, stroke, diabetes, fatty liver conditions such as fatty liver deposits, obesity or a combination thereof.
  • the compositions of the invention is preferably used to treat or prevent hypertriglyceridemia and associated diseases, such as diabetes, in humans.
  • cardiovascular diseases may include myocardial infarction, coronary heart disease, atherosclerosis, arteriosclerosis, and cerebrovascular diseases or conditions, including stroke, cerebral thrombosis or memory loss due to stroke.
  • the present invention also provides compositions for modulating serum lipid and lipoprotein levels in a human in need of lowering the lipid and lipoprotein levels to a healthy normal range.
  • the composition of the invention is used to reduce serum cholesterol and serum triglyceride levels in a human.
  • the compositions of the invention are particularly useful for the treatment of geriatric patients and postmenopausal women.
  • the present invention further provides compositions for treating a human afflicted by shortness of breath, asthenic breathing, lethargy, dizziness, chronic headache, loss of appetite, limb swelling, tightness and distention, and abdominal distention, or a combination thereof.
  • the preventive or therapeutic dose of traditional red rice or improved red rice in the treatment or prevention of diseases and in the management of serum lipid and lipoprotein levels will vary with the condition to be treated and the severity of the condition to be treated.
  • the dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose range of red rice, for the conditions described herein is from about 0.1 g to about 5 g administered in single or divided doses orally.
  • a preferred oral daily dose range should be from about 0.3 g to about 4 g, while most preferably an oral daily dose should be about 1.2 to about 2.5 g.
  • two capsules each containing 0.6 g of red rice may be taken orally twice a day to obtain the preferred dose.
  • a course of treatment should be at least 4 weeks. It may be necessary to use dosages outside these ranges in some cases as will be apparent to those skilled in the art. Further, it is noted that the nutritionist, dietitian, clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient response.
  • the present invention encompasses new uses of traditional red rice, and novel red rice products.
  • the present invention encompasses compositions of novel or improved red rice products as dietary supplements.
  • the red rice products provide the individual with a means for maintaining normal or healthy levels of serum cholesterol and triglycerides despite intrinsic deterioration, e.g., from aging and extrinsic factors such as stress, lack or exercise and poor nutrition.
  • the dietary supplements also provide means for preventing, or reducing the likelihood or experiencing, the diseases discussed above.
  • the dietary supplements can be used to prevent weight gain or obesity.
  • the dietary supplements containing red rice products are particularly useful for the elderly and postmenopausal women.
  • the dietary supplements should be taken daily for at least four weeks and can be used permanently on a daily basis.
  • a daily dose is from about 0.1 g to about 5.0 g; preferably about 1 to about 4 g; and most preferably about 1.2 to about 2.4 grams per day.
  • compositions of the present invention comprise a red rice product, or an extract thereof, as active ingredient, and may also contain a pharmaceutically acceptable carrier or excipient and, optionally, other ingredients.
  • the formulation can comprise 10 mg lovastatin.
  • compositions comprising red rice can be added directly to foods so that a therapeutically effective amount of red rice is ingested during normal meals. Any methods known to those skilled in the art may be used to add or incorporate red rice to natural or processed foods.
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of a red rice product, as a powder or granules, or as a solution or a suspension in an aqueous liquid, a nonaqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion.
  • the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • compositions of the present invention may additionally include binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); binders or fillers (e.g., lactose, pentosan, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate).
  • binding agents e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • binders or fillers e.g., lactose, pentosan, microcrystalline cellulose or calcium hydrogen phosphate
  • lubricants e.g., magnesium stearate, talc or silica
  • disintegrants e.g., potato starch or sodium starch
  • Liquid preparations for oral administration can take the form of, for example, solutions, syrups or suspensions, or they can be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g., lecithin or acacia), nonaqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid).
  • suspending agents e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats
  • emulsifying agents e.g., lecithin or acacia
  • nonaqueous vehicles e.g., almond oil, oily esters, ethyl alcohol
  • any dosage form may be employed for providing the patient with an effective dosage of the red rice product.
  • Dosage forms include tablets, capsules, dispersions, suspensions, solutions, capsules and the like. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers as described above are employed.
  • the compounds of the present invention may also be administered by controlled release means. However, the most preferred oral solid preparations are capsules.
  • a tablet may be prepared by compression or molding, optionally, with one more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine red rice in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent.
  • the composition is a capsule containing 0.3 g of red rice in powder form.
  • Red rice was shown to dramatically decrease serum total cholesterol (TC) of endogenous hyperlipidemic rabbits, remarkably decrease TC and total triglyceride (TG) of exogenous hyperlipidemic rabbits, inhibit formation of arteriosclerosis plaque and lipid deposition in liver in hyperlipidemic rabbits, and decrease serum TC and TG of hyperlipidemic quails.
  • TC total cholesterol
  • TG total triglyceride
  • a LD 50 value cannot be determined.
  • the highest tolerance dose of red rice in mice is over 16 g/kg, which is 533 times over the dose used in clinical treatment.
  • rats were continuously force-fed red rice for four months; no rats died or showed toxic symptoms due to this drug.
  • Hematological indices, main viscera indices, blood biological indices, routine uroscopy and pathological examination did not show any differences between experimental groups and control groups.
  • the following two examples contain the methodologies and results of two human clinical trials that were carried out in China.
  • the trials were designed to determine the efficacy of a red rice product in modulating circulating serum lipid and lipoprotein levels in humans, in resolving symptoms according to traditional Chinese medicine, and in establishing the safety of a red rice product.
  • the total number of patients enrolled was 446.
  • the ratio of male versus female was 1.38:1 and the average age was 56.0 ⁇ 9 years old.
  • the ratio of male versus female was 1.49:1 and average age was 56.4 ⁇ 9.1 years old.
  • P>0.05 found in baseline parameters including age, sex and course of disease, serum lipid and lipoprotein levels.
  • the group receiving red rice treatment took two Xuezhikang capsules orally, twice a day for 8 weeks.
  • the control group took three Jiaogulan tablets twice a day for 8 weeks. All the patients maintained the same lifestyle and habits as before.
  • BLTN blood urea nitrogen
  • SGPT serum glutamic pyruvic transaminase
  • ALT serum glucose
  • CK creatinine kinase
  • Table 2 Comparison of serum lipid and lipoprotein levels after treatment Parameter Group Case No.
  • Table 1 shows a comparison of overall efficacy.
  • the efficacy scores for curing or reducing total serum cholesterol and total triglyceride level in the treated group were greater than that in the control group.
  • the score for normalizing or increasing HDL-C, level and the score for reducing Atherosclerotic Index in the treated group were also much better than the control (P ⁇ 0.001).
  • Table 2 indicates that both Xuezhikang-treated and control groups showed marked desirable changes in the levels of TC, TG, (TC - HDL-C)/HDL-C, HDL-C serum levels markedly.
  • the effectiveness of Xuezhikang was found to be superior to that of Jiaogulan.
  • apoA-I apolipoprotein as a-I
  • apoB apolipoprotein B
  • Statistical results show a significant difference in apoA-I levels after a four week treatment. ApoB levels were reduced somewhat in both groups, however, these reductions are not statistically significant.
  • the treated group showed better improvement of apolipoprotein B and apoA-I/apoB over the control.
  • BUN blood urea nitrogen
  • SGPT serum glutamic pyruvic transaminase
  • ALT serum glucose
  • CK creatinine kinase
  • a lipid regulating agent known in traditional Chinese medicine was used as a positive control.
  • the efficacy score in the Xuezhikang-treated group was much higher than that in the control group (P ⁇ 0.001). Comparing the baseline, in Xuezhikang-treated group, serum level of high density lipoprotein cholesterol was elevated by 19.6% and total cholesterol, total triglyceride, low density lipoprotein cholesterol and Atherosclerosis Index were reduced by 23%, 36.5%, 28.5% and 34.2%, respectively. It was also observed that the higher the abnormality of the lipid and lipoprotein serum level, the more dramatic the modulation of lipid and lipoprotein levels can be achieved by Xuezhikang therapy. Xuezhikang can also reduce apolipoprotein B level, blood sedimentation and blood sedimentation K-value.
  • red rice was as a safe, effective agent for modulating serum lipid and lipoprotein levels.
  • Red rice can also be used as a therapeutic agent for coronary artery disease and cerebrovascular disease caused by hyperlipidemia and/or athyrosis because red rice not only significantly reduced plasma TC, TG and Atherosclerosis Index, but also markedly raised plasma apolipoprotein in as a-I level.
  • the total number of patients enrolled was 116. There were 84 patients in the treated group and 32 patients in the control group. No difference of distribution in age, sex and course of disease were found between the two groups.
  • the treated group (84 cases) took two Xuezhikang capsules (i.e., a red rice product of the present invention) twice a day.
  • the control group (32 cases) took three Jiaogulan tablets (ShanXi factory of Chinese materia medica, lot number: 940730) twice a day.
  • the course of treatment was eight weeks.
  • the measurements of serum lipid and lipoprotein levels and other scoring were performed prior to the therapy, and at four weeks and at eight weeks after therapy.
  • the safety tests were conducted before and after therapy.
  • a fasting venous blood sample was collected; patients were not allowed to consume alcohol or food with a high fat content in the last meal.
  • BUN blood and urea nitrogen
  • SGPT serum glutamic pyruvic transaminase
  • ALT serum glucose
  • CK creatinine kinase
  • Table 5 shows a comparison of the overall efficacy score of the two groups.
  • Table 6 shows a comparison of efficacies as defined by the standards of traditional Chinese medicine.
  • Table 6 Comparison of efficacy Symptoms Red Rice Control Statistics Before After Vanish% Before After Vanish % Asthenic breathing 35 15 57.1 12 6 50 >0.05 Limbs tight 37 16 56.8 13 7 46.2 >0.05 Oppressed feeling in chest 37 16 56.8 9 5 44.4 * Chest pain 8 1 87.5 2 1 50 * Loss of appetite 11 4 63.6 3 2 33.3 * Distension & swelling stomach 31 11 64.5 7 6 14.3 * Pale tongue 54 34 37 17 12 31.3 >0.05 Purple dot on tongue 9 4 55.6 3 4 0 * Thick-whitish fur 21 16 23.8 11 6 45.5 >0.05 Thick-slimy fur 11 8 27.3 5 4 0 Slippery & string-like pulse 28 22 21.4 13 8 33.3 * Weak-thread pulse 24 16 33.3 8 3 62.6 * Slippery-fine pulse 28 16 42.9 9 8 11.1 * *P ⁇ 0.05 vs control The percentage of patients who reported elimination of the symptoms
  • the scores for curing or reducing total serum cholesterol level in the treated group were greater than that in the control group.
  • Table 10 shows the changes in Atherosclerotic Index which is the ratio of (TC-HDL-C)/HDL-C.
  • Table 11 shows the effect of Xuezhikang on regulating serum lipid and lipoprotein levels (X+/-S). Table 11: Regulating Effect of Xuezhikang on serum lipid and lipoprotein (X ⁇ S) Group Time Point Case No. TC (mg/dl) Case No. TG(mg/dl) Case No. HDL-c (mg/dl) Case No.
  • Table 11 indicates that Xuezhikang improved TC, TG, (TC - HDL-C)/HDL-C, HDL-C serum levels markedly, but control group only improved TG significantly. Xuezhikang therapy was found to regulate TC, LDL-C more effectively than the control.
  • Table 12 shows the efficacy of Xuezhikang therapy on different baseline of serum lipid and lipoprotein. Table 12: Efficacy comparison of Xuezhikang therapy on different baseline of serum lipid and lipoprotein.
  • TC mg/g
  • TG mg/g
  • HDL-C mg/dl

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Claims (5)

  1. Procédé de production de riz rouge amélioré, ledit procédé comprenant les étapes suivantes :
    - fournir une souche de Monascus productrice de lovastatine sélectionnée parmi le groupe constitué de Monascus albidus CGMCC n°0317 ; Monascus ruber van Tieghem CGMCC n°0315 ; CGMCC n°0316 ; Monascus paxii Lingelsheim AS 3.4453 ; Monascus fuliginosus AS 3.569, AS 3.1098, AS 3.2091, AS 3.2093, AS 3.2134 et IFFI 05035 ;
    - mettre en culture ladite souche de Monascus dans un milieu de culture comprenant du riz à une température de 15°C à 35°C pendant une période de 2 à 20 jours pour donner de la levure de riz rouge brut ; et
    - sécher ledit riz rouge brut pour donner du riz rouge amélioré.
  2. Procédé selon la revendication 1, dans lequel ledit milieu de culture comprend en outre :
    - 2% à 6 % de sucre ;
    - 2% à 7% de source de carbone supplémentaire sélectionné parmi le groupe constitué de glycérol, de malt, de jus de pomme de terre ;
    - 0% à 3% de peptone ;
    - 0% à 3% de jus de viande épais ; et
    - 2% à 4% d'antimousse.
  3. Procédé selon la revendication 1, dans lequel lesdites souches mises en culture à 30°C à 34°C pendant 2 à 4 jours, sont ensuite mises en culture à 20°C à 25°C pendant au moins 4 jours.
  4. Procédé selon la revendication 1, qui comprend en outre :
    - l'extraction dudit riz rouge amélioré avec une solution d'éthanol pour donner un extrait d'éthanol ; et
    - le séchage dudit extrait.
  5. Procédé selon la revendication 1, dans lequel ladite solution d'éthanol comprend 75% à 95% d'éthanol aqueux.
EP98954688A 1997-11-06 1998-11-06 Compositions contenant des produits fermentes a base de riz rouge et procedes associes Expired - Lifetime EP1044009B8 (fr)

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US965202 1997-11-06
PCT/IB1998/001918 WO1999023996A2 (fr) 1997-11-06 1998-11-06 Compositions contenant des produits fermentes a base de riz rouge et procedes associes

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DK1044009T3 (da) 2008-04-28
US20030194413A1 (en) 2003-10-16
CA2309100A1 (fr) 1999-05-20
DE69838988T2 (de) 2009-01-15
EP1044009B8 (fr) 2008-02-20
JP2003521217A (ja) 2003-07-15
WO1999023996A2 (fr) 1999-05-20
US6046022A (en) 2000-04-04
PT1044009E (pt) 2008-03-20
DE69838988D1 (de) 2008-02-21
EP1044009A2 (fr) 2000-10-18
US6632428B1 (en) 2003-10-14
BR9815272A (pt) 2000-12-19
EP1044009A4 (fr) 2001-07-18
AU1170999A (en) 1999-05-31
CA2309100C (fr) 2009-09-15
WO1999023996A3 (fr) 1999-08-19
ATE383164T1 (de) 2008-01-15
ES2299217T3 (es) 2008-05-16

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